Prostate cancer (PCa) is a major source of cancer morbidity and mortality in men. Androgen-deprivation, the main therapeutic intervention for advanced PCa patients, inevitably fails and the disease subsequently recurs in a hormone-refractory form that often leads to the death of the patient. Our goal of identifying novel molecular mechanisms through which PCa cells develop resistance to hormone therapy has led to the discovery of a unique gene product referred to as protocadherin-PC (PCDH-PC) that is upregulated in apoptosis- and hormone-resistant prostate cancer cells as well as in actual hormone-resistant tumors from patients. PCDH-PC is remarkable because of its male-specific nature (it is encoded on the human Y- chromosome) and because its expression is associated with activation of wnt- and Akt- signaling pathways as well as with the activation of a transdifferentiation process in which PCa cells acquire neuroendocrine (NE) cell-like characteristics. These behaviors (wnt-/Akt-signaling and NE phenotype) are found in advanced and hormone-resistant PCa cells and the work in this project will increase our understanding of PCDH-PC's role in hormone-resistant PCa. Experiments in Specific Aim 1 will explore the mechanism through which PCDH-PC upregulates wnt signaling by characterizing the domains of PCDH-PC that are involved in wnt signaling control. Experiments in Specific Aim 2 will characterize the effects of PCDH-PC expression on gene expression patterns in PCa cells and determine how PCDH-PC expression influences their malignant behavior. Work under Specific Aim 3 will develop a transgenic mouse model in which PCDH-PC expression is targeted to the prostate to determine whether expression of this gene product is sufficient to induce prostatic neoplasia or whether co-expression of this gene in existing transgenic prostate cancer models (LADY 12T-7 or PTEN knockout) leads to the development of more aggressive prostate cancers. By defining the mechanism through which PCDH-PC exerts its effects on the PCa cell and characterizing the malignant behaviors that are elicited by PCDH-PC expression, we will show the importance of this gene product for prostate cancer progression and better define it as a target for the development of therapeutics to control hormone-refractory disease. [unreadable] [unreadable] [unreadable]